Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

• Published in: Molecular cell Vol. 57; no. 5; pp. 901 - 911
• Main Authors: VanderLinden, Ryan T., Hemmis, Casey W., Schmitt, Benjamin, Ndoja, Ada, Whitby, Frank G., Robinson, Howard, Cohen, Robert E., Yao, Tingting, Hill, Christopher P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2015
• Subjects: Amino Acid Sequence; Binding Sites - genetics; Catalytic Domain; Crystallography, X-Ray; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation; Humans; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Models, Molecular; Molecular Sequence Data; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Ubiquitin - chemistry; Ubiquitin - metabolism; Ubiquitin Thiolesterase - chemistry; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.01.016

The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to the proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the roles of UCH37 in the unrelated proteasome and INO80 complexes. [Display omitted] •The DUB UCH37 is a subunit of the 26S proteasome and the INO80 chromatin remodeler•Proteasome/RPN13 and INO80/NFRKB bind similarly to the UCH37 C-terminal helices•RPN13 activates UCH37 through contacts that enhance ubiquitin binding•NFRKB inhibits UCH37 by occluding ubiquitin binding and disrupting the active site VanderLinden et al. determined structures and performed biochemical studies of the essential deubiquitylase UCH37 with its 26S proteasome and INO80 chromatin remodeler binding partners. The mechanistic basis for how UCH37 is activated in the proteasome complex but repressed in the INO80 complex is explained.